Citations

PURPOSE External beam radiation therapy (EBRT) has gained delayed acceptance as a recommended first-line treatment modality for patients with hepatocellular carcinoma (HCC), given limited evidence that it improves overall survival (OS). We analyzed individual patient data (IPD) from an international cohort to assess OS among patients with HCC treated with EBRT. METHODS We performed a systematic review of publications that assessed EBRT, met prespecified technical standards for HCC, and reported OS (search date December 15, 2022). Corresponding authors were invited to submit IPD for the study. We performed Kaplan-Meier survival analyses to determine OS and restricted mean survival time (RMST) stratified by Barcelona Clinic Liver Cancer (BCLC) stage and treatment status (ie, treatment-naïve and experienced). We performed random effects Cox proportional hazards modeling to assess clinical characteristics associated with OS. RESULTS Data were provided on 4,913 patients treated with EBRT with a median follow-up time of 5.0 years. The median OS was 6.8 years (95% CI, 5.7 to 8.7) for BCLC-0 and 4.6 years (95% CI, 4.1 to 5.1) for BCLC-A. Among treatment-naïve patients, the median OS was not reached (95% CI, 8.6 to not reached) for BCLC-0 and was 5.4 years (95% CI, 4.5 to 6.7) for BCLC-A. In multivariable models, more advanced BCLC stage, higher tumor burden, worse performance status, and Child-Pugh class B or C were associated with a higher risk of mortality. Ablative radiation dose and more recent year of treatment were associated with a reduced risk of death. CONCLUSION To our knowledge, this study represents the largest multinational cohort of patients with HCC treated with EBRT. OS outcomes with EBRT for very early- and early-stage HCC appear to be comparable with resection, thermal ablation, and other ablative locoregional therapies. These data support the inclusion of EBRT in the BCLC HCC clinical decision-making process.

Abstract Solitary plasmacytoma of bone (SPB) is a localized plasma cell neoplasm associated with a substantial risk of progression to multiple myeloma (MM), yet the role of adjuvant systemic therapy following definitive radiation therapy (RT) remains undefined. We conducted a randomized phase III trial (Alliance A061402) to evaluate whether the addition of systemic therapy with ixazomib, lenalidomide, and dexamethasone (IXA-LEN-DEX) to zoledronic acid (ZA) improves outcomes compared with ZA alone in patients with SPB and minimal (< 10%) bone marrow plasma cell involvement following RT. Patients were randomized to receive six 28-day cycles of IXA-LEN-DEX-ZA or ZA alone. The primary endpoint was time to progression (TTP) to MM. The study was closed early due to poor accrual after enrolling 11 patients (IXA-LEN-DEX-ZA, n = 5; ZA, n = 6). All patients completed RT and planned treatment without dose reductions. The combination regimen was well tolerated, with limited grade ≥ 3 toxicities, including hypophosphatemia and lymphopenia. At follow-up extending beyond 4 years, the 1- and 4-year progression rates to MM in the IXA-LEN-DEX-ZA arm were 0% and 33%, respectively, compared with 37.5% and 58.3% at 1 and 2 years in the ZA-alone arm. Although underpowered, these findings demonstrate the feasibility and tolerability of an all-oral adjuvant systemic regimen in SPB and provide prospective data supporting further investigation of systemic strategies to delay progression to MM.

ABSTRACT Bispecific T cell engagers (BTEs) induce MHC‐independent cytotoxicity by bridging T cells to tumor cells via binding a T cell–activating receptor and a tumor‐associated antigen. BTEs have proven effective in hematologic malignancies and some solid tumors, yet their potential in glioblastoma (GBM) is largely unexplored. We developed a fully humanized BTE (hBTE) targeting interleukin‐13 receptor alpha 2 (IL13RA2), a tumor‐associated antigen widely expressed in GBM and associated with poor prognosis. In vitro, hBTE activated T cells and induced antigen‐dependent cytokine release and cytotoxicity against IL13RA2‐positive GBM cells. In vivo, hBTE showed robust target‐specific activity and markedly prolonged survival in primary and recurrent GBM xenograft models, without detectable off‐target local or systemic toxicity. Beyond GBM, hBTE also exhibited antitumor activity in IL13RA2‐expressing solid tumors, demonstrating selective tumor accumulation and therapeutic efficacy in models of breast cancer brain metastases and extracranial lung cancer. This work highlights the therapeutic potential of BTEs in IL13RA2‐expressing tumors and establishes a strong preclinical rationale for advancing hBTE therapy toward clinical translation in GBM and other tumors.

Abstract Introduction. This study aimed to characterize the population pharmacokinetics (PopPK) of nab-paclitaxel following the administration of the nano-immunoconjugate nab-paclitaxel-bevacizumab to patients with unresectable stage IV melanoma or gynecological cancers (NCT02020707). The core objective was to characterize the population mean drug concentration-time profile, understand the variability in drug concentrations and identify factors that explain differences in paclitaxel plasma clearance. Also, we sought to explore the impact of the nano-immunoconjugate formulation on paclitaxel clearance. Methods. Using Pumas AI - an advanced pharmacokinetic software program, integrating Machine Learning methods - a PopPK analysis was conducted using concentration-time data collected from 29 subjects, (681 concentration measurements). Patients received 75 - 175 mg/m2 (total dose, 160 - 360 mg). Data were fitted to a 2-compartment model based biphasic decline observed in plasma concentration following intravenous administration. A critical requirement for the model was the inclusion of saturable elimination to accurately describe the drug’s disposition. A comprehensive modeling workflow was implemented, starting with base models (mixed vs. non-linear clearance), followed by the sequential addition of covariates (Age, Sex, BSA, Tumor, Cycle). The Parsimony Principle was applied to select the most appropriate model. Results. Population estimates for paclitaxel clearance and volume of distribution were 41.7 L/hr and 312 L, respectively. The analysis found paclitaxel clearance higher when compared with published data for nab-paclitaxel alone (21.1 or 25 L/h/m2; Sparreboom et al, CCR 11:4136, 2005 and Ando et al, CCP 69:457, 2012). A covariate model incorporating BSA and Gender is the best. For every 2 m2 increase in BSA, linear clearance (CL) increases by 6.9%. Females have 16.6% lower CL than males, which successfully characterized systematic differences in PK between subgroups of subjects. Conclusion. The administration of nab-paclitaxel via the nano-immunoconjugate formulation led to increased clearance for paclitaxel consistent with known clearance mechanisms for therapeutic antibodies. The differences in drug clearance among patients were primarily attributable to covariates BSA and gender. These findings are crucial for identifying safe and effective dosing regimens and informing future clinical simulations. Citation Format: Mohd Beshr Chama, Matthew Stephen Block, Vera J. Suman, Joel M. Reid. Population pharmacokinetics of nab-paclitaxel following administration of a nano-immunoconjugate with bevacizumab [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 301.

Abstract Background and Aims Stroke and systemic embolism are recognized but poorly characterized complications of atrial fibrillation (AF) and left atrial flutter (AFL) catheter ablation. Their incidence, outcomes, and procedural associations remain insufficiently defined. Methods Retrospective global registry was initiated by the European Heart Rhythm Association Scientific Committee. A secure database captured data from ablation centres worldwide on general AF and left AFL ablation activity, as well as detailed information on patients with symptomatic embolic events between 2017 and 2024. Results Overall, 204 centres reported 335 743 ablation procedures and 550 embolic events (incidence 0.16%). Centre-level rate ranged from 0% to 3.1%. Most events were cerebral (94%), followed by peripheral (5%), and combined (1%). Coronary air embolism accounted for 62% of all peripheral events. Intraprocedural events occurred in 93 patients (17%), within 72 h in 357 (78%) and beyond 72 h in 100 (22%); 128 cases (23%) were diagnosed after hospital discharge. Nonparoxysmal AF (0.23% vs 0.15%; P &lt; .001), centre experience, and ablation energy source (radiofrequency, 0.16%; cryoballoon, 0.16%; pulsed field ablation, 0.25%; laserballoon, 0.88%; P &lt; .001) were associated with embolic risk. Median NIHSS score after stroke was 4 (interquartile range, 2–9). Three-month follow-up was available for 518 patients with embolism (95%): 181 (35%) had sequelae and 16 (3%) died. Conclusions Symptomatic embolic events are infrequent but associated with significant morbidity and mortality. Most events occur early, though a substantial proportion arise later. Higher event rates were observed with laser and possibly with pulsed field ablation. A greater centre experience was associated with a lower embolism incidence.

Importance Adjuvant chemotherapy regimens may be administered after pancreatic resection for adenocarcinoma arising from intraductal papillary mucinous neoplasms (A-IPMNs), although the evidence supporting their use is limited. Objective To evaluate the survival benefit associated with contemporary adjuvant chemotherapy regimens after resection in A-IPMNs between 2017 and 2023. Design, Setting, and Participants This retrospective cohort study was an international, multicenter study with 69 participating centers across Europe, North America, South America, and the Asia-Pacific region. Patients undergoing resection for A-IPMNs were included. Data were analyzed from May to August 2025. Intervention Contemporary adjuvant chemotherapy regimens, such as gemcitabine-capecitabine (GemCap); 5-fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFIRINOX), modified FOLFIRINOX (mFOLFIRINOX), and S-1. Main Outcome and Measure Overall survival (months). Results Among 1321 patients (median [IQR] age 70 [63 to 76] years; 713 males [54.0%] and 608 females [46.0%]), 781 patients (59.1%) received adjuvant chemotherapy, while in 181 patients (13.7%) it was omitted due to poor patient fitness. Of patients who received adjuvant chemotherapy, 568 patients (72.6%) received contemporary regimens, including GemCap (232 patients [29.7%]), FOLFIRINOX (176 patients [22.5%]), mFOLFIRINOX (71 patients [9.1%]), and S-1 (70 patients [9.0%]). The median (IQR) follow-up for the cohort was 64.2 (40.4 to 85.0) months, and the median overall survival was 73.8 months (95% CI, 66.4 to 81.9 months). After 90-day landmark analysis and exclusion of patients ineligible for chemotherapy, adjuvant chemotherapy vs no adjuvant chemotherapy (propensity score–matched populations, 243:243 patients) was not associated with improved overall survival (median, 82.3 months; 95% CI, 78.2 months to not applicable [NA] vs not reached; 95% CI, 75.3 months to NA; P = .58). Contemporary regimens vs no adjuvant chemotherapy (propensity score–matched populations, 309:309 patients) was not associated with longer survival, and a mean survival benefit greater than 4.2 months over 5 years was excluded (difference in restricted mean survival, 1.26 months; 95%, −1.72 to 4.24 months). Treatment outcomes did not vary by chemotherapy regimen or disease characteristic (eg, N stage or carbohydrate antigen 19-9 level). Conclusions and Relevance In this study, contemporary adjuvant chemotherapy was not associated with improved overall survival in A-IPMNs, and a randomized clinical trial is indicated.

ABSTRACT Background Sunlight has profound impacts on physical and mental health, beyond vision, including effects on circadian rhythms, alertness, mood, and sleep. A family history of any mood disorders is strongly associated with psychiatric disorders including bipolar disorder. The purpose of this study was to evaluate the association between a family history of any mood disorder in patients with bipolar I disorder and solar insolation at varied international onset locations. Methods Data for this analysis were available from 5842 patients with a diagnosis of bipolar I disorder obtained at 83 collection sites in both hemispheres. This included 4752 patients from 71 collection sites in the northern hemisphere and 1090 patients from 12 collection sites in the southern hemisphere. Patient data variables were obtained from records or interviews. Solar insolation data were obtained from The National Aeronautics and Space Administration (NASA) Power database for each onset location, and the ratio of the mean monthly minimum/mean monthly maximum solar insolation was calculated. Typically, the ratio is largest near the equator (little yearly change in solar insolation) and smallest near the poles (large yearly change in solar insolation). Results A significant relationship was found between a family history of any mood disorder, the ratio of the mean monthly minimum/mean monthly maximum solar insolation, and gender. The odds of a family history of mood disorder increased as patient location nears the poles and decreased near the equator. Female gender also increased the odds of having a family history of a mood disorder. Conclusions This study highlighted the association between family history, solar insolation, and gender in international patients with bipolar I disorder. Given the profound effects of sunlight on human health, the family of patients with bipolar disorder who live in the same location with the same solar insolation, and especially females, may be at increased risk for a mood disorder.

Background Large language models (LLMs) are entering clinical workflows, yet their alignment with medical-ethical principles is unclear. Objective To evaluate how LLMs reconcile deontological and utilitarian reasoning in medically adapted “Trolley dilemma” scenarios. Methods We tested 14 LLMs, including GPT-o1-preview and DeepSeek-R1-Distill-Llama, using five medically adapted Trolley dilemmas sourced from philosophical and real-world scenarios. Each model generated 10 independent answers per case (overall 700 responses). Responses were forced to “yes” (utilitarian) or “no” (deontological). The primary outcome was the proportion of utilitarian choices. χ 2 tests compared models. Results LLM responses varied. Some models, such as GPT-4 and Gemma, selected the utilitarian option in 20% of cases, while others, like Qwen-2-7B, reached 80% ( p < .001). GPT-o1-preview and DeepSeek-R1-Distill-Llama selected utilitarian responses in 44% and 38% of cases, respectively. Some models selected the consequence-maximizing option in vignettes where doing so required overriding consent or endorsing intentional harm within the scenario framing. Seven of the fourteen models tested recommended impermissible medical actions, including nonconsensual limb amputation, killing a healthy person for organ harvesting, and transferring a patient to hospice against their wishes, in 44 of 700 outputs (6.3 %). Conclusions In this constrained forced-choice stress test, models occasionally endorsed boundary-violating actions within the vignette framing. These results do not generalize to routine clinical decision-making, but motivate further benchmarked evaluation of refusal behavior and boundary constraints in ethically sensitive medical contexts. We must carefully define how these models influence clinical decisions, establish robust ethical guidelines for their use, and ensure that fundamental ethical norms are not compromised.